The complex choreography of macrophage function is not only determined by its genetic composition, but is also strongly influenced by epigenetic mechanisms that have emerged as key factors regulating macrophage behavior. Here, Creative Biolabs shares knowledge about macrophage epigenetic regulation and explores how it affects macrophage development, plasticity, and response to various environmental cues.

Macrophage Development and Lineage Specification

The process of macrophage lineage specification involves a series of well-coordinated steps guided by epigenetic regulators.

Fig. 1 Epigenetic lineage determination and signal stimulation collaboratively control the enhancers of macrophages.¹

• Key transcription factors such as PU.1 and C/EBPα spearhead the labeling of enhancer regions, making them available for subsequent gene expression. These transcription factors collaborate with epigenetic modifiers to establish open chromatin conformations that enable the activation of lineage-specific genes.
• Histone modifications, such as acetylation and methylation, are integral to macrophage differentiation. Enhancer regions of macrophage-specific genes undergo histone acetylation, leading to chromatin relaxation and increased gene transcription. Conversely, histone methylation can activate or repress gene expression depending on the specific lysine residues targeted. The dynamic interplay of these modifications ensures appropriate expression of genes required for macrophage identity and function.

Epigenetic Reprogramming in Macrophage Polarization

Macrophage polarization is regulated by epigenetic modifications.

• The epigenetic landscape of M1 polarization is characterized by increased histone acetylation at pro-inflammatory gene loci. This acetylation is facilitated by histone acetyltransferase (HAT), which relaxes chromatin, allowing transcription factors such as NF-κB to bind and drive gene expression. DNA demethylation also contributes to the proinflammatory profile of M1 macrophages.
• Epigenetic regulation of M2 polarization involves histone methylation and DNA methylation. Histone H3 trimethylation at lysine 4 (H3K4me3) is enriched at the promoters of M2-associated genes and promotes their transcription. In addition, DNA methyltransferases can affect M2 polarization by methylating and silencing genes associated with the M1 phenotype.

Epigenetic Dysregulation in Inflammatory Diseases

Dysregulated macrophage responses contribute to the pathogenesis of a variety of inflammatory diseases, including atherosclerosis, obesity, and autoimmune diseases. Importantly, epigenetic modifications are associated with these dysregulated responses.

• In atherosclerosis, epigenetic changes in macrophages may lead to the accumulation of lipid-rich foam cells in the arterial wall. DNA methylation patterns in atherosclerotic lesions differ from those in healthy arteries, affecting lipid metabolism and expression of inflammation-related genes.
• In obesity, epigenetic modifications of macrophages may lead to chronic low-grade inflammation in adipose tissue and exacerbate insulin resistance.

Therapeutic Implications

The complex role of epigenetics in macrophage function opens avenues for therapeutic intervention. Targeting epigenetic modifiers may modulate macrophage responses in a variety of diseases.

• Epigenetic therapies may be used to restore the balance of macrophage function in inflammatory diseases.
• For example, HDAC inhibitors have shown promise in attenuating inflammatory responses in models of sepsis and autoimmune disease.

Epigenetic mechanisms have a huge impact on macrophage biology. As our understanding of epigenetics continues to expand, so does our ability to utilize these mechanisms therapeutically. Contact us to decipher the epigenetic code of macrophages!

References

1. Chen, Siyuan, et al. "Epigenetic regulation of macrophages: from homeostasis maintenance to host defense." Cellular & molecular immunology 17.1 (2020): 36-49.
2. Hoeksema, Marten A., and Menno PJ de Winther. "Epigenetic regulation of monocyte and macrophage function." Antioxidants & redox signaling 25.14 (2016): 758-774.